AQP4 (Aquaporin-4) is the principal water channel protein expressed in the central nervous system, primarily in astrocytic end-feet that surround blood vessels and the pial surface. It plays a critical role in brain water homeostasis, cerebrospinal fluid circulation, and neuroinflammation.
| AQP4 Protein |
|---|
| Protein Name | Aquaporin-4 |
| Gene | [AQP4](/genes/aqp4) |
| UniProt ID | [P55064](https://www.uniprot.org/uniprot/P55064) |
| PDB Structures | 1xzx, 2d57 |
| Molecular Weight | 34 kDa |
| Subcellular Localization | Plasma membrane (astrocytic end-feet), basolateral membrane |
| Protein Family | Aquaporin (MIP) family |
¶ Domain Architecture
AQP4 is a monomeric water channel that assembles as a tetramer. Each monomer contains six transmembrane alpha-helices with both N- and C-termini facing the cytosol. The protein has two half-helices that form the pore, with conserved NPA (Asn-Pro-Ala) motifs in the middle of the transmembrane helices that are characteristic of aquaporins.
AQP4 is the dominant water channel in the brain and plays several essential roles:
- Brain Water Homeostasis: Regulates water flow across the blood-brain barrier and between intracellular and extracellular compartments
- Cerebrospinal Fluid Circulation: Facilitates CSF flow through the ventricular system and subarachnoid space
- Astrocytic Function: Expressed in astrocytic end-feet surrounding cerebral blood vessels, forming the glia limitans perivascularis
- Potassium Buffering: Cooperates with Kir4.1 potassium channels in astrocytic potassium homeostasis
- Neurovascular Coupling: Links neuronal activity to changes in cerebral blood flow through astrocytic signaling
- AQP4 expression is altered in AD brain, with mislocalization from perivascular to somatic membranes
- Impaired perivascular AQP4 leads to reduced glymphatic clearance of amyloid-beta
- Loss of polar AQP4 distribution correlates with reduced interstitial fluid clearance
- AQP4 deficiency accelerates amyloid plaque deposition in mouse models
- AQP4 upregulation in PD substantia nigra may contribute to neuroinflammation
- Altered water homeostasis affects dopaminergic neuron survival
- Potential role in Lewy body formation through impaired protein clearance
- AQP4 expression changes in motor cortex and spinal cord
- Dysregulated water homeostasis contributes to excitotoxicity
- Astrocyte reactivity involves AQP4 redistribution
- AQP4 is the target of neuromyelitis optica (NMO) autoantibodies
- Loss of AQP4 in NMO leads to extensive astrocyte damage
- Role in blood-brain barrier breakdown and demyelination
- AQP4 upregulation contributes to cytotoxic edema
- Dysregulated water flux exacerbates secondary neuronal damage
- AQP4 inhibitors: TGN-020 and AqB013 are experimental AQP4 blockers under investigation
- Anti-edema agents: AQP4 modulators being explored for traumatic brain injury
- Viral vector-mediated AQP4 modulation for neuroprotection
- CRISPR-based editing to restore proper AQP4 localization
- AQP4 autoantibodies serve as diagnostic marker for neuromyelitis optica
- Cerebrospinal fluid AQP4 levels as potential neurodegeneration biomarker
- Nico et al., AQP4 in brain edema (2003)
- Iliff et al., Glymphatic clearance (2012)
- Papadopoulos & Verkman, AQP4 function (2007)
- Mader et al., NMO-IgG and AQP4 (2009)
- Yang et al., AQP4 and Alzheimer's (2011)